scholarly journals Fibrillin-1 regulates the bioavailability of TGFβ1

2007 ◽  
Vol 176 (3) ◽  
pp. 355-367 ◽  
Author(s):  
Shazia S. Chaudhry ◽  
Stuart A. Cain ◽  
Amanda Morgan ◽  
Sarah L. Dallas ◽  
C. Adrian Shuttleworth ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Solid Phase ◽  
Binding Studies ◽  
Tgfβ Signaling ◽  
Intact Cells ◽  
Altered Expression ◽  
Tgfβ Receptor ◽  
Fibrillin 1 ◽  
Cell Layers ◽  
Tgf Β1

We have discovered that fibrillin-1, which forms extracellular microfibrils, can regulate the bioavailability of transforming growth factor (TGF) β1, a powerful cytokine that modulates cell survival and phenotype. Altered TGFβ signaling is a major contributor to the pathology of Marfan syndrome (MFS) and related diseases. In the presence of cell layer extracellular matrix, a fibrillin-1 sequence encoded by exons 44–49 releases endogenous TGFβ1, thereby stimulating TGFβ receptor–mediated Smad2 signaling. This altered TGFβ1 bioavailability does not require intact cells, proteolysis, or the altered expression of TGFβ1 or its receptors. Mass spectrometry revealed that a fibrillin-1 fragment containing the TGFβ1-releasing sequence specifically associates with full-length fibrillin-1 in cell layers. Solid-phase and BIAcore binding studies showed that this fragment interacts strongly and specifically with N-terminal fibrillin-1, thereby inhibiting the association of C-terminal latent TGFβ-binding protein 1 (a component of the large latent complex [LLC]) with N-terminal fibrillin-1. By releasing LLC from microfibrils, the fibrillin-1 sequence encoded by exons 44–49 can contribute to MFS and related diseases.

scholarly journals Skeletal Deformities in Osterix-Cre;Tgfbr2f/f Mice May Cause Postnatal Death

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 975
Author(s):  
Kara Corps ◽  
Monica Stanwick ◽  
Juliann Rectenwald ◽  
Andrew Kruggel ◽  
Sarah B. Peters
Keyword(s):  
Transforming Growth Factor ◽  
Skeletal Development ◽  
Transforming Growth Factor Β ◽  
Tgfβ Signaling ◽  
Skeletal Deformities ◽  
Tooth Abnormalities ◽  
Pathological Analysis ◽  
Diaphragmatic Muscle ◽  
Proliferation And Differentiation ◽  
Tgfβ Receptor

Transforming growth factor β (TGFβ) signaling plays an important role in skeletal development. We previously demonstrated that the loss of TGFβ receptor II (Tgfbr2) in Osterix-Cre-expressing mesenchyme results in defects in bones and teeth due to reduced proliferation and differentiation in pre-osteoblasts and pre-odontoblasts. These Osterix-Cre;Tgfbr2f/f mice typically die within approximately four weeks for unknown reasons. To investigate the cause of death, we performed extensive pathological analysis on Osterix-Cre- (Cre-), Osterix-Cre+;Tgfbr2f/wt (HET), and Osterix-Cre+;Tgfbr2f/f (CKO) mice. We also crossed Osterix-Cre mice with the ROSA26mTmG reporter line to identify potential off-target Cre expression. The findings recapitulated published skeletal and tooth abnormalities and revealed previously unreported osteochondral dysplasia throughout both the appendicular and axial skeletons in the CKO mice, including the calvaria. Alterations to the nasal area and teeth suggest a potentially reduced capacity to sense and process food, while off-target Cre expression in the gastrointestinal tract may indicate an inability to absorb nutrients. Additionally, altered nasal passages and unexplained changes in diaphragmatic muscle support the possibility of hypoxia. We conclude that these mice likely died due to a combination of breathing difficulties, malnutrition, and starvation resulting primarily from skeletal deformities that decreased their ability to sense, gather, and process food.

scholarly journals Identification of a microRNA signature in renal fibrosis: role of miR-21

2011 ◽  
Vol 301 (4) ◽  
pp. F793-F801 ◽  
Author(s):  
Abolfazl Zarjou ◽  
Shanzhong Yang ◽  
Edward Abraham ◽  
Anupam Agarwal ◽  
Gang Liu
Keyword(s):  
Epithelial Cells ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Response To Treatment ◽  
Tubular Epithelial Cells ◽  
Altered Expression ◽  
Tnf Α ◽  
Tgf Β1

Renal fibrosis is a final stage of many forms of kidney disease and leads to impairment of kidney function. The molecular pathogenesis of renal fibrosis is currently not well-understood. microRNAs (miRNAs) are important players in initiation and progression of many pathologic processes including diabetes, cancer, and cardiovascular disease. However, the role of miRNAs in kidney injury and repair is not well-characterized. In the present study, we found a unique miRNA signature associated with unilateral ureteral obstruction (UUO)-induced renal fibrosis. We found altered expression in UUO kidneys of miRNAs that have been shown to be responsive to stimulation by transforming growth factor (TGF)-β1 or TNF-α. Among these miRNAs, miR-21 demonstrated the greatest increase in UUO kidneys. The enhanced expression of miR-21 was located mainly in distal tubular epithelial cells. miR-21 expression was upregulated in response to treatment with TGF-β1 or TNF-α in human renal tubular epithelial cells in vitro. Furthermore, we found that blocking miR-21 in vivo attenuated UUO-induced renal fibrosis, presumably through diminishing the expression of profibrotic proteins and reducing infiltration of inflammatory macrophages in UUO kidneys. Our data suggest that targeting specific miRNAs could be a novel therapeutic approach to treat renal fibrosis.

scholarly journals Cholesterol deprivation induces TGFβ signaling to promote basal differentiation in pancreatic cancer

2019 ◽  
Author(s):  
Linara G. Cornell ◽  
Suraj Peri ◽  
Diana Restifo ◽  
Alena Klochkova ◽  
Tiffiney R. Hartman ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Cholesterol Metabolism ◽  
Cholesterol Biosynthesis ◽  
Ductal Adenocarcinoma ◽  
Tgfβ Signaling ◽  
Pancreatic Development ◽  
Mesenchymal Phenotype ◽  
Tgfβ Receptor ◽  
Growth Factor Beta

SummaryOncogenic transformation alters the metabolism of cellular nutrients to sustain tumor growth. We here define a mechanism by which modifications in cholesterol metabolism control the formation of pancreatic ductal adenocarcinoma (PDAC). Disruption of distal cholesterol biosynthesis by means of conditional inactivation ofNsdhlin mice bearing a tumor-inducingKrasmutation (KrasG12D) prevented PDAC formation in the context of a heterozygousTrp53f/+genotype without impairing normal pancreatic development. In mice with pancreaticNsdhlablation and homozygous loss ofTrp53, the emerging tumors presented with the aggressive basal (mesenchymal) phenotype as opposed to the classic (glandular) PDAC. This paralleled significantly reduced expression of cholesterol metabolic pathway genes in human basal PDAC subtype. Mechanistically, we demonstrate that genetic or metabolic cholesterol deprivation stabilizes the transforming growth factor beta (TGFβ) receptor to activate pro-mesenchymal effectors in human and murine PDAC, providing a direct mechanism by which cholesterol metabolism can condition tumor differentiation.

Inhibition of type I and III IP3Rs by TGF-β is associated with impaired calcium release in mesangial cells

2000 ◽  
Vol 278 (6) ◽  
pp. F1022-F1029 ◽  
Author(s):  
Kumar Sharma ◽  
Tracy A. Mc Gowan ◽  
Lewei Wang ◽  
Muniswamy Madesh ◽  
Vince Kaspar ◽  
...  
Keyword(s):  
Growth Factor ◽  
Calcium Release ◽  
Transforming Growth Factor ◽  
Prolonged Exposure ◽  
Mesangial Cells ◽  
Free Calcium ◽  
Type I ◽  
Intact Cells ◽  
Permeabilized Cells ◽  
Tgf Β1

Inositol 1,4,5-trisphosphate receptors (IP3Rs) mediate cytosolic free calcium concentration ([Ca2+]c) signals in response to a variety of agonists that stimulate mesangial cell contraction and proliferation. In the present study, we demonstrate that mesangial cells express both type I and III IP3Rs and that these receptors occupy different cellular locations. Chronic treatment with transforming growth factor-β1 (TGF-β1; 10 ng/ml, 24 h) leads to downregulation of both type I and III IP3Rs as measured by immunoblot and confocal analysis. TGF-β1 treatment does not affect IP3 levels, and downregulation of type I IP3R is not due to enhanced degradation of the protein, as the half-life of type I IP3R is unchanged in the presence or absence of TGF-β1. Functional effects of TGF-β1-induced downregulation of the IP3Rs were evaluated by measuring [Ca2+]c changes in response to epidermal growth factor (EGF) in intact cells and sensitivity of [Ca2+]c release to IP3in permeabilized cells. TGF-β1 pretreatment led to a significant decrease of [Ca2+]c release induced by EGF in intact cells and by submaximal IP3 (400 nm) in permeabilized cells. Total IP3-sensitive [Ca2+]cstores were not changed, as assessed by stimulation with maximal doses of IP3 (10.5 μm) and thapsigargin-mediated calcium release in permeabilized cells. We conclude that prolonged exposure to TGF-β1 leads to downregulation of both type I and III IP3Rs in mesangial cells and this is associated with impaired sensitivity to IP3.

A Potent Pan-TGFβ Neutralizing Monoclonal Antibody Elicits Cardiovascular Toxicity in Mice and Cynomolgus Monkeys

2020 ◽  
Vol 175 (1) ◽  
pp. 24-34 ◽  
Author(s):  
Mayur S Mitra ◽  
Karla Lancaster ◽  
Adeyemi O Adedeji ◽  
Gopinath S Palanisamy ◽  
Rutwij A Dave ◽  
...  
Keyword(s):  
Small Molecule ◽  
Transforming Growth Factor ◽  
Small Molecule Inhibitors ◽  
Recovery Period ◽  
Transforming Growth Factor Β ◽  
Cardiovascular Toxicity ◽  
Tgfβ Signaling ◽  
Cynomolgus Monkeys ◽  
Tgfβ Receptor ◽  
Neutralizing Monoclonal Antibody

Abstract Transforming growth factor β (TGFβ) signaling has been recently shown to reduce antitumor response to PD-L1 blockade, leading to a renewed enthusiasm in developing anti-TGFβ therapies for potential combination with cancer immunotherapy agents. Inhibition of TGFβ signaling in nonclinical toxicology species is associated with serious adverse toxicities including cardiac valvulopathies and anemia. Previously, cardiovascular toxicities have been thought to be limited to small molecule inhibitors of TGFβ receptor and not considered to be a liability associated with pan-TGFβ neutralizing monoclonal antibodies (mAbs). Here, we report the toxicity findings associated with a potent pan-TGFβ neutralizing mAb (pan-TGFβ mAb; neutralizes TGFβ1, 2, and 3) after 5 weekly intravenous doses of 10, 30, and 100 mg/kg, followed by a 4-week recovery period, in mice and cynomolgus monkeys. Mortality was observed due to acute bleeding and cardiovascular toxicity in mice at ≥ 30 mg/kg and prolonged menstruation in female monkeys at 100 mg/kg. Additional findings considered to be on-target exaggerated pharmacology included generalized bleeding and cardiovascular toxicity in mice and monkeys; histopathologic changes in the teeth, tongue, and skin in mice; and abnormal wound healing and microscopic pathology in the bone in monkeys. Importantly, our data indicate that the cardiovascular toxicities associated with the inhibition of TGFβ signaling are not limited to small molecule inhibitors but are also observed following administration of a potent pan-TGFβ inhibiting mAb.

scholarly journals SMAD2 promotes myogenin expression and terminal myogenic differentiation

Development ◽  
2021 ◽  
Vol 148 (3) ◽  
pp. dev195495
Author(s):  
Émilie Lamarche ◽  
Hamood AlSudais ◽  
Rashida Rajgara ◽  
Dechen Fu ◽  
Saadeddine Omaiche ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Myogenic Differentiation ◽  
Transforming Growth Factor Β ◽  
Acute Injury ◽  
Tgfβ Signaling ◽  
Primary Myoblasts ◽  
Tgfβ Receptor ◽  
Differentiation Marker ◽  
Tgfβ Superfamily

ABSTRACTSMAD2 is a transcription factor, the activity of which is regulated by members of the transforming growth factor β (TGFβ) superfamily. Although activation of SMAD2 and SMAD3 downstream of TGFβ or myostatin signaling is known to inhibit myogenesis, we found that SMAD2 in the absence of TGFβ signaling promotes terminal myogenic differentiation. We found that, during myogenic differentiation, SMAD2 expression is induced. Knockout of SMAD2 expression in primary myoblasts did not affect the efficiency of myogenic differentiation but produced smaller myotubes with reduced expression of the terminal differentiation marker myogenin. Conversely, overexpression of SMAD2 stimulated myogenin expression, and enhanced both differentiation and fusion, and these effects were independent of classical activation by the TGFβ receptor complex. Loss of Smad2 in muscle satellite cells in vivo resulted in decreased muscle fiber caliber and impaired regeneration after acute injury. Taken together, we demonstrate that SMAD2 is an important positive regulator of myogenic differentiation, in part through the regulation of Myog.

scholarly journals Molecular Biomarkers for Weight Control in Obese Individuals Subjected to a Multiphase Dietary Intervention

2017 ◽  
Vol 102 (8) ◽  
pp. 2751-2761 ◽  
Author(s):  
Jennifer Bolton ◽  
Emilie Montastier ◽  
Jérôme Carayol ◽  
Sophie Bonnel ◽  
Lucile Mir ◽  
...  
Keyword(s):  
Weight Loss ◽  
Messenger Rna ◽  
Weight Control ◽  
Dietary Intervention ◽  
Transforming Growth Factor ◽  
Plasma Concentrations ◽  
Enzyme Linked Immunosorbent Assay ◽  
Circulating Biomarkers ◽  
Altered Expression ◽  
Tgf Β1

Abstract Context Although calorie restriction has proven beneficial for weight loss, long-term weight control is variable between individuals. Objective To identify biomarkers of successful weight control during a dietary intervention (DI). Design, Setting, and Participants Adipose tissue (AT) transcriptomes were compared between 21 obese individuals who either maintained weight loss or regained weight during the DI. Results were validated on 310 individuals from the same study using quantitative reverse transcription polymerase chain reaction and protein levels of potential circulating biomarkers measured by enzyme-linked immunosorbent assay. Intervention Individuals underwent 8 weeks of low-calorie diet, then 6 months of ad libitum diet. Outcome Measure Weight changes at the end of the DI. Results We evaluated six genes that had altered expression during DI, encode secreted proteins, and have not previously been implicated in weight control (EGFL6, FSTL3, CRYAB, TNMD, SPARC, IGFBP3), as well as genes for which baseline expression differed between those with good and poor weight control (ASPN, USP53). Changes in plasma concentrations of EGFL6, FSTL3, and CRYAB mirrored AT messenger RNA expression; all decreased during DI in individuals with good weight control. ASPN and USP53 had higher baseline expression in individuals who went on to have good weight control. Expression quantitative trait loci analysis found polymorphisms associated with expression levels of USP53 in AT. A regulatory network was identified in which transforming growth factor β1 (TGF-β1) was responsible for downregulation of certain genes during DI in good controllers. Interestingly, ASPN is a TGF-β1 inhibitor. Conclusions We found circulating biomarkers associated with weight control that could influence weight management strategies and genes that may be prognostic for successful weight control.

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